Cutaneous squamous cell carcinoma (cSCC), a form of non-melanoma skin cancer, is the second most common form of cancer in the United States, with over 700,000 cases diagnosed annually. The incidence of SCC continues to rise, increasing 50%-200% in the last several decades. Further, patients with metastatic disease have a poor survival rate and are susceptible to secondary cancers. Thus, it is becoming increasingly important to identify genetic factors that increase ones susceptibility to development and progression of SCC. Tpl2, a gene in the mitogen-activated protein kinase (MAPK) family, can function as a tumor suppressor gene in skin cancer. Mice with a Tpl2 deletion have both an increased incidence of skin carcinogenesis and increased propensity for tumor metastasis. The long term goal of this project is to understand the manner in which Tpl2 functions as a tumor suppressor gene in skin cancer. Our central hypothesis is that stromal-epithelial interactions and alterations in HGF/c-MET signaling are necessary to drive skin cancer development and progression in Tpl2-/- mice. Our first aim will use 2D and 3D co-culture experiments to help characterize the role of stromal fibroblasts in Tpl2-related skin cancer. Our second aim will use in vivo experimentation with a pharmacological inhibitor selective for c-MET to determine if blocking HGF/c-MET signaling can suppress tumorigenesis, inflammation, and cancer progression in Tpl2-/- mice. Further, the in vitro genetic manipulation studies proposed in the second aim will help compliment the in vivo studies and elucidate whether Tpl2 modulates TGF- suppression of HGF/c-MET signaling. These studies will contribute to our understanding of how Tpl2 acts as a tumor suppressor gene in skin cancer. Identifying how Tpl2 interacts with other genes and pathways that contribute to skin carcinogenesis will allow for the design of more targeted therapeutics.